is a complex neuropsychiatric disorder to which an as-yet-unknown number of genes contribute, interacting with each other and the environment. Linkage analyses have implicated several chromosomal regions as harboring schizophrenia susceptibility loci although rarely at levels commensurate with proposed thresholds for genome-wide significance. We systematically recruited Arab Israeli families multiply affected with schizophrenia from the catchment area of a Regional Mental Health Center. Clinical diagnoses were established by semistructured interviews and all other available sources of information under narrow, core and broad categories. Using 350 microsatellite markers, spaced at an average of 10.3 cM, we performed an autosomal scan in 155 subjects from 21 families. Linkage analysis employed affects only, multipoint, nonparametric (model-free) and also parametric (dominant and recessive) approaches. We detected significant evidence for a schizophrenia susceptibility gene at chromosome 6q23 with a nonparametric LOD score (NPL) of 4.60 (P ¼ 0.000004) under the broad diagnostic category and a parametric LOD score of 3.33 (dominant model). Under the core diagnostic category the NPL was 4.29 (P ¼ 0.00001) and the LOD score 4.16 (dominant model). We also detected suggestive evidence for linkage at chromosome 10q24 under the broad diagnostic category (NPL 3.24, P ¼ 0.0008; heterogeneity LOD score, dominant model 2.65, a ¼ 0.82). Additionally, NPL scores 42.0 were observed at chromosome 2q37, 4p15-16, 7p22, 9q21-22 and 14q11.1-11.2. The linkage we detected at chromosome 6q23 fulfills the criteria for genome-wide significance and is located approximately midway between loci suggested by a previous significant report at chromosome 6q25 and findings located more centromerically at 6q21-22.
Anxiety involves complex, incompletely understood interactions of genomic, environmental, and experience-derived factors, and is currently being measured by psychological criteria. Here, we report previously nonperceived interrelationships between expression variations and nucleotide polymorphisms of the chromosome 7q21-22 acetylcholinesterase-paraoxonase 1 (ACHE-PON1) locus with the trait-and state-anxiety measures of 461 healthy subjects from the Health, Risk Factors, Exercise Training, and Genetics Family Study. The AChE protein controls the termination of the stress-enhanced acetylcholine signaling, whereas the PON protein displays peroxidase-like activity, thus protecting blood proteins from oxidative stress damages. Serum AChE and PON enzyme activities were both found to be affected by demographic parameters, and showed inverse, reciprocal associations with anxiety measures. Moreover, the transient scores of state anxiety and the susceptibility score of trait anxiety both appeared to be linked to enzyme activities. This finding supported the notion of corresponding gene expression relationships. Parallel polymorphisms in the ACHE and PON1 genes displayed apparent associations with both trait-and state-anxiety scores. Our findings indicate that a significant source of anxiety feelings involves inherited and acquired parameters of acetylcholine regulation that can be readily quantified, which can help explaining part of the human variance for state and trait anxiety.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.